CLINICAL INVESTIGATIONS AND PRECISION THERAPEUTICS PROJECT SUMMARY/ABSTRACT The overall goals of the Clinical Investigations and Precision Therapeutics (CIPT) Program are to translate outstanding science into early phase trials, to develop new diagnostic, prevention, and therapeutic strategies for human cancer, and to promote bidirectional translation from bench to bedside and back. CIPT provides a translational bridge between the basic science and population science programs and the clinic, and conducts its own programmatically aligned translational research. CIPT is unique in its centralization of experience in the development of early phase clinical trials with expertise in molecular biology, genomics, imaging analysis, systems biology, statistics, and biomarker development. CIPT members translate scientific findings to create new paradigms at the bench and in the clinic, and are positioned within this multidisciplinary framework to access the expertise necessary for high impact translational research. High impact translational projects are prioritized for institutional support. CIPT has 60 members from 22 Departments and 7 Schools. CIPT research is well funded with $5.6M annual direct peer-reviewed grant support, $4.4M of which is cancer- focused (9 multi-PI), with $2.3M from the NCI (8 R01-equivalent/7 PIs, one UM1). In the last funding period CIPT members published 929 papers, 42% of which were collaborative (29% intra- and 25% inter- collaborations) with 51% collaborative with other institutions. This represents an increase in both total and collaborative publications compared with last project period. Impactful science includes discovery of compounds that reactivate specific conformational mutants of p53 in collaboration with the Cancer Pharmacology Program (CP); development of rational combinations of MAPK pathway and apoptosis inhibition, and targeting cancer metabolism by inhibiting autophagy in collaboration with the Cancer Metabolism and Growth Program, (CMG); and identification of mechanisms of resistance to PARP inhibitors in BRCA1 mutant cancers in collaboration with Genome Instability and Cancer Genetics Program (GICG). These approaches are being assessed in the clinic and in mouse models. CIPT investigators worked with CMG and GICG investigators to identify novel markers of response to immune checkpoint therapy, including presence of DNA polymerase-epsilon mutations in endometrial cancer. Collaboration with biomedical engineers in CP led to development of a classifier to help guide treatment of early stage ER+ breast cancer based on computational analysis of digital histology images. Collaboration with the Cancer Prevention and Control Program (CPC) led to studies evaluating the impact of mental illness on breast cancer outcome in the elderly. Finally, clinical investigation of immune checkpoint therapy in Merkel cell carcinoma led to FDA approval of avelumab for advanced disease. CIPT science is fueled by translation of findings in the Research Programs, and reverse translation of clinical findings to identify novel molecular mechanisms of response and resistance. CPC, Part I: Narrative, Page 1 of 1; DRAFT 1/19/18 11:56 AM